Concomitant myeloproliferative neoplasm with eosinophilia, B and T cell lymphoblastic lymphoma/leukemia and mast cell proliferation driven by <i>ZMYM2::FGFR1</i> rearrangement
Authors: Giuseppe G. Loscocco, Stefano Ascani, Francesco Mannelli, Magda Zanelli, Giada Rotunno, Raffaella Santi, Alessandro M. Vannucchi
Journal: American Journal of Hematology (2023)

According to the 5th edition of the World Health Organization and the 2022 International Consensus Classifications, Myeloid/lymphoid neoplasms with eosinophilia and tyrosine kinase (TK) gene fusions (MLNs) are a group of rare and heterogenous hematological neoplasms characterized by constitutive TK activity due to gene fusions involving mainly PDGFRA, PDGFRB, FGFR1 but also JAK2, FLT3 and ETV6. To date, sixteen fusion partners to FGFR1 have been reported, with t(8;13)(p11;q12) involving ZMYM2 being the most common.1, 2 Although the clinical presentation of FGFR1-rearranged MLNs is highly proteiform from having the features of a myeloproliferative neoplasm (MPN) to myelodysplastic syndrome (MDS), MDS/MPN, acute myeloid leukemia, T- or B-cell lymphoblastic lymphoma/leukemia(LBL), or mixed phenotype acute leukemia; moreover, some cases of associated systemic mastocytosis (SM)/mast cell proliferation were reported.3-6 Eosinophilia is characteristic, but not invariably present. In most cases, the outcome is poor, and conventional therapies are largely ineffective. Here we report a case of concomitant MPN with eosinophilia, B and T cell lymphoblastic lymphoma/leukemia and mast cell proliferation driven by ZMYM2::FGFR1 rearrangement. A 74-year-old woman without a significant medical history was referred to our Institution because of progressive enlarged bilateral cervical and inguinal lymph nodes (LNs), asthenia, fever, night-sweats, and a 10-kg weight loss over the past 2 months. Clinical examination showed bilateral cervical and inguinal LNs, bruises on the lower extremities and spleen and liver palpable at 5 cm and 3 cm from costal margin, respectively. Whole-body computed tomography (CT) scan documented a diffuse lymphadenopathy of the bilateral neck, abdominal, para-aortic, iliac, and inguinal regions along with hepatosplenomegaly, showing an intense metabolic activity by 18-fluorodeoxyglucose (FDG)-positron emission tomography (PET) scan. Blood count revealed leukocytosis (white blood cells 52 × 109/L, 10% myelocytes, 8% metamyelocytes, 64% neutrophils, 4% lymphocytes, 6% monocytes, 12% eosinophils), and thrombocytopenia (platelet count 55 × 109/L), whereas hemoglobin was within normal range (13 g/dL). Serum lactate dehydrogenase was increased (600 U/L, normale range 135–214). Biopsies of cervical LN and bone marrow (BM) were performed. At microscopic evaluation, the architecture of the LN was effaced by a monomorphic proliferation of medium-sized lymphoid cells with scanty cytoplasm and dispersed chromatin with the following immunophenotype: TdT+, CD99+, CD1a+/−, CD10−/+, CD34-, CD2+, CD3+, CD5+, CD7+, CD4+/−, CD8−/+, CD20-, CD30-, BCL6+/−, cyCD79a-, CD117-, LMO2-, c-MYC- and high proliferation index (Ki67 98%). Eosinophils were admixed. The diagnosis of T-lymphoblastic lymphoma (T-LBL) was made. (Image 1A–F). BM biopsy revealed a hypercellular marrow (90%) with a relatively reduced erythropoiesis, prevalent granulopoiesis with hypereosinophilia and increase in megakaryocytes with defects in nuclear segmentation. BM evaluation also identified a small component (5% of total BM cellularity) of B lymphoblasts (TdT+, CD34+, PAX5+, CD79a+, CD10+, CD20-, CD3-, CD1a-, MPO-) along with spindle-shaped mast cells, single and in small clusters, expressing tryptase and CD117 (Image 2A–F). Flow-cytometry evaluation confirmed the presence of a blastic B-cell population (CD45dim, CD56dim), representing 10% of total BM cellularity, with the follow immunophenotyping: CD34+, CD117−/+, HLA-DR+, CD13+, CD33−/+, CD15-, CD64−/+, CD14-, CD5-, CD7−/+, CD19 −/+, CD22−/+, CD10−/+, CD38+, CD25+, CD2-, cyCD3-, TdT−/+, cyCD79a+, CD105−/+. Moreover, mast cells were increased (1.13% of total BM cellularity) and aberrantly expressed CD25, whereas CD2 and CD30 were negative. BM cytogenetic documented the following karyotype: 46,XX,t(8;13)(p11;q12)[16]/46,XX [5]. ZMYM2::FGFR1 translocation was confirmed by Fluorescent In Situ Hybridization (FISH) using chromosome 8 and 13 probes and corresponding fusion transcript was detected by Next Generation Sequencing (NGS) analysis. BM droplet digital polymerase chain reaction (ddPCR) analysis did not reveal the presence of cKIT p. D816V mutation nor other non-canonical cKIT mutations; conversely, NGS analysis on BM documented the presence of the following variants: RUNX1 c.610C > T (p.Arg204*) with a variant allele frequency (VAF) of 56% and PHF6 c.487C > T (p.Arg163Cys) with a VAF of 48%. Serum tryptase was mildly elevated at 31.2 μg/L (normal range 0–13.4). The patient received two courses of multi-agent chemotherapy with cyclophosphamide, vincristine, and prednisone (CVP), with a substantial refractoriness. Later on, she was evaluated for enrollment in the multicenter open-label, single-arm FIGHT-203 trial with FGFR1-3 inhibitor pemigatinib (NCT03011372).7 To our knowledge we report herein the second case of ZMYM2::FGFR1 rearranged neoplasm presenting as concurrent MPN with eosinophilia, B and T-LBL and mast cell proliferation. In the recent years, some studies documented that mast cell proliferation can be seen in most cases of MLNs, particularly in those with PDGFRA rearrangements. In most instances, the mast cells showed an aberrant CD25 expression and were usually scattered and spindle shaped, but sometimes they constituted dense clusters with histopathological features typical of SM. Moreover, almost all these cases lacked the cKIT p.D816V mutation and lacked clinical feature of SM.5, 6 Therefore, categorization of these rare cases as SM is challenging. Building upon these observations the ICC authors suggested to classify cKIT p.D816V negative mast cell proliferation within cases of MLN, as an intrinsic manifestation of the disease. On the contrary, cKIT p.D816V positive cases should be considered as a true associated SM.2 From a practical point of view, when mast cell proliferation is associated with features of MPN or eosinophilia and cKIT p.D816V is negative, it is highly recommended to test for PDGFRA firstly, and then also for PDGFRB and FGFR1 gene fusions.2, 5, 6 Accordingly, this reported case of mast cell proliferation, owing to the absence of cKIT p.D816V and the presence of ZMYM2::FGFR1 pathogenetic translocation in a pluripotent stem cell virtually capable of differentiation into myeloid cells, lymphoid cells and also mastocytes, should be more properly regarded as an intrinsic clinical manifestation of MLN rather than an associated SM. Cases of MLNs, although rare and highly heterogenous, should be suspected early and rapid confirmatory genetic diagnosis should be obtained promptly since, while usually refractory to conventional chemotherapies, they may respond to targeted therapies as pemigatinib in FGFR1, and imatinib in PDGFRA and PDGFRB rearranged cases.8 This research was supported by AIRC 5 × 1000 called “Metastatic disease: the key unmet need in oncology” to MYNERVA project, grant number #21267 (MYeloid NEoplasms Research Venture AIRC). A detailed description of the MYNERVA project is available at http://www.progettomynerva.it. G.G.L. and A.S. received speaker fees from Novartis; F.M. received advisory board fees from Blueprint and Novartis. A.M.V. received speaker fees from Novartis, AOP Health, Incyte, AbbVie, GlaxoSmithKline (GSK), and Bristol Myers Squibb (BMS) and advisory board fees from Novartis, Incyte, AOP Orphan Pharmaceuticals, AbbVie, GSK, BMS, Roche, Blueprint. The other authors declare no conflict of interest. The funders had no role in the design of the study, in the collection, analyses, interpretation of data and in the writing of the present manuscript.